Disease relevance of XAF1

• RESULTS: IFN-alfa stimulates XAF1 promoter activity in the colon cancer cells Lovo and SW1116 dose-dependently [1].
• Results: Down-regulation of XAF1 in association with hypermethylation was detected in 3 of 4 human gastric cancer cell lines and 6 of 8 colon cancer cell lines [2].
• Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas [3].
• Furthermore, the overexpression of the zinc-finger portion of XAF1 blocked IFN-dependent sensitization of A375 melanoma cells to the proapoptotic effects of TRAIL [4].
• XAF1 expression was lower in gastrointestinal cancers than in normal tissues with the mechanism unclear [5].
• Promoter CpG site methylation was observed frequently in both cell lines and tumor tissues including many LOH tumors, suggesting that biallelic inactivation of XAF1 might be common in colorectal cancers [6].

High impact information on XAF1

• Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus [7].
• XAF1 is ubiquitously expressed in normal tissues, but is present at low or undetectable levels in many different cancer cell lines [7].
• Our results indicate that XAF1 may be important in mediating the apoptosis resistance of cancer cells [7].
• XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities [7].
• The aim of this study was to examine the novel pattern of methylation of XAF1 in gastric and colon cancers and locate the important CpG sites for transcriptional regulation and tumor progression [2].

Chemical compound and disease context of XAF1

• All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer [1].

Biological context of XAF1

• We recently isolated, by yeast two-hybrid screening, a novel 34-kDa zinc finger protein, XIAP-associated factor 1 (XAF1) [8].
• Microsatellite analysis of the xaf1 locus using the NCI 60 cell line panel revealed significantly decreased heterozygosity at all three polymorphic markers tested, suggesting that allelic loss of the xaf1 gene is prevalent in cancer cell lines [8].
• The xaf1 gene consists of seven exons spanning 18 kb [8].
• XAF1 messenger RNA is present in normal tissues but undetectable in various cancers and thus poses a potential tumor suppressor gene [2].
• Conclusions: A cluster of methylated CpG sites instead of CpG islands located in the promoter area resulted in gene silencing of XAF1, and CpGs at -2nd, -1st, and +3rd positions are functionally more important in its transcriptional regulation [2].

Anatomical context of XAF1

• Examination of the same NCI cell line panel for xaf1 RNA expression demonstrated that cancer cell lines exhibited very low levels of mRNA relative to normal human liver [8].
• The regulation of IAPs and XAF1 varied after axotomy of the sciatic nerve; in the neonate, there was a significant loss of IAP in the injured motoneurons as opposed to the adult, in which there was only a moderate decrease [9].

Associations of XAF1 with chemical compounds

• Methylation status of XAF1 was determined by methylation-specific PCR (MSP) and bisulfite DNA sequencing PCR analysis [2].
• XAF1 expression enhanced the apoptotic response of tumor cells to chemotherapeutic agents, such as etoposide or 5-FU [10].

Physical interactions of XAF1

• Moreover, pretreatment with antioxidants suppressed HSF1 binding activity and increased the transcriptional activity and expression of XAF1 [5].
• Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family [7].

Regulatory relationships of XAF1

• Both the caspase inhibiting and the anti-apoptotic abilities of XIAP were found to be blocked by overexpressed XAF1 [8].
• HSF1 down-regulates XAF1 through transcriptional regulation [5].
• This implicates a role for the mitochondrial apoptotic pathway, consistent with the ability of Bcl2 to block Xaf1 induced apoptosis [11].

Other interactions of XAF1

• We propose that a high level of XIAP to XAF1 expression in cancer cells may provide a survival advantage through the relative increase of XIAP anti-apoptotic function [8].
• The xaf1 locus was further refined to YAC 746C10, approximately 3 cM distal to TP53 [8].
• These results suggested that IFN-dependent induction of XAF1 strongly influenced cellular sensitivity to the proapoptotic actions of TRAIL [4].
• The expression of XAF1 and HSF1 was negatively correlated in gastrointestinal cancer cell lines [5].
• However, IFNs induced high levels of XAF1 protein predominantly in cell lines sensitive to the proapoptotic effects of IFN-beta [4].

Analytical, diagnostic and therapeutic context of XAF1

• Fluorescence in situ hybridization analysis localized the xaf1 locus at 17p13.2, telomeric to the p53 gene [8].
• Methods: XAF1 expression was detected by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis [2].
• Site-directed mutagenesis of IRF-E-XAF1 abrogates native and IFN-induced promoter activity and binding capacity [1].
• In opposition, the overexpression of exogenous XAF1 in adult motoneurons totally abrogated the natural resistance of these cells to axotomy [9].
• METHODS: The expression of XAF1 in four human colon cancer cell lines (Colo205, Colo320, SW1116, LoVo) and in samples from 70 patients with CRC was analyzed by reverse transcriptase-polymerase chain reaction [12].

References